Abstract 6896: A pan-KRAS degrader for the treatment of KRAS-mutant cancers

Abstract KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data reveal that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of the PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting “undruggable” proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers. Citation Format: Mu-Sheng Zeng, Jie Yang, Qiao-Li Wang Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng. A pan-KRAS degrader for the treatment of KRAS-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6896.